We are studying the normal differentiation and regulatory interactions of B cells, T cells, and NK cells to gain information that can be used to analyze lymphoid malignancies, immunodeficiency diseases, and other disorders of immunoregulation. A large panel of monoclonal antibodies has been prepared against B-cell determinants, including antibodies to Ig isotypes, allotypes, and idiotypes and VH subgroups, as well as non-Ig determinants. These are used to define the genesis of pre-B and B cells in fetal liver and bone marrow and their subsequent migration and differentiation in peripheral lymphoid tissues. The therapeutic potential of anti-Ig antibodies is being explored in selected patients with B-cell malignancies. B-cell activation by anti-Ig antibodies in combination with various monokines and lymphokines is being explored. Ig isotype switching will be studied at both cellular and molecular levels in leukemic pre-B cell clones, cultures of mouse pre-B cells, and normal B cells. Our studies so far suggest that isotype switching is nonrandom and non-T cell dependent and usually involves direct switches from IgM to other isotypes; sequential isotype switching appears to be uncommon. Isotype-committed B cells were found to be selectively induced by helper T cells or soluble factors. Studies of human B cell and plasma cell maliganancies suggest that these malignancies: (1)\all have their origin in bone marrow; (2)\involve a stepwise progression of transformation events; and (3)\clonal involvement in each case occurs prior to isotype switching. Children with pre-B leukemia were shown to have a significantly poorer prognosis than children with "null" cell leukemia, and this may be associated with a chromosomal 1;19 translocation. A monoclonal antibody, HNK-1 or Leu 7, was prepared against a cell surface molecule of 110 kilodaltons, which is selectively expressed by human granular lymphocytes having natural killer cell activity. It has been used to examine the development, distribution, and function of NK cells and to define functionally deficient NK cells in patients with Chediak-Higashi syndrome and AIDS. Hemophilia patients treated with Factor VIII concentrates were found to have an isolated increase in circulating T suppressor cells, and in some cases this has preceded the development of AIDS. (LB)